Phase I Study of Ceritinib combined with Trametinib in Patients with Advanced ALK- or ROS1-Positive Non-Small Cell Lung Cancer

Open AccessPublished:November 18, 2022DOI:
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      In patients with non-small cell lung cancers (NSCLC) harboring oncogenic ALK or ROS1 rearrangements, tyrosine kinase inhibitors have yielded high response rates and improvements in progression-free survival compared to cytotoxic chemotherapy, however, acquired resistance eventually develops. In preclinical models, ALK and MEK co-inhibition was able to overcome ALK inhibitor resistance.


      A phase I study of the ALK/ROS1 inhibitor ceritinib and the MEK inhibitor trametinib in patients with refractory NSCLC harboring ALK or ROS1 fusions was initiated. A 3 + 3 dose escalation scheme was employed. Two dose levels were investigated. The primary endpoint was to determine the safety and tolerability of the combination.


      Nine patients (n = 8 ALK+, n = 1 ROS1+) were enrolled in the study and completed at least 1 cycle of therapy. The most common adverse events (AE, all grades) were diarrhea (n = 9; 100%), rash (n = 8; 89%), abdominal pain (n = 5; 56%), and elevated AST/ALT (n = 4; 44%). The overall response rate was 22% while disease control rate was 56%. Median duration of response was 7.85 months. The median progression free survival (PFS) was 3.0 months (95% CI: 1.5 – 7.0 months). The median overall survival (OS) was 8.9 months (95% CI: 2.0 - N.R.)


      Data from this trial indicates that the combination of ceritinib and trametinib revealed no unexpected toxicities and that a tolerable dose could be identified. A subset of patients appeared to obtain clinical benefit from this treatment after progression on prior ALK/ROS1 inhibitor treatment.

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